Archival Record of NIMH Research Workshop (Summary) May 10-11, 1999

Critical Questions for Discussion:

A. Focus on Bipolar Disorder:

1. How early can bipolar disorder be diagnosed?
2. What is the predictive value of the early manifestations of bipolar illness in children (before puberty) and in adolescents?
3. What is the risk/benefit ratio of treating children and adolescents with "prodromal" symptoms? Which treatments should be considered? For how long?
4. What is the potential impact of early treatment on course of illness?
5. Mood stabilizers, such as lithium, carbamazepine, and valproate, have been shown to be effective in treating acute episodes of bipolar disorder and in preventing relapse and recurrence of episodes in adults. How and to which extent can this knowledge be extrapolated to children and adolescents? Which are the critical studies that need to be conducted in order to fully establish valid treatment guidelines for treating and preventing manic-depressive illness in children and in adolescents?
6. What are the ethical implications of early treatment vs. non-treatment? What are the ethical aspects of conducting research in this area?

B. Focus on Schizophrenia:

1. How early can schizophrenia be diagnosed?
2. What is the predictive value of the early manifestations of psychosis in children (before puberty) and in adolescents?
3. What is the risk/benefit ratio of treating children and adolescents with early manifestations of psychosis ("prodromal" symptoms)? Which treatments should be considered? For how long?
4. What is the potential impact of early treatment on course of illness?
5. Atypical antipsychotics have a more favorable profile of effects and side effects than classic neuroleptics, but data in children are limited. What are the main safety concerns that must be addressed in pediatric patients? Using which study designs?
6. What are the ethical implications of early treatment vs. non-treatment? What are the ethical aspects of conducting research in this area?

Main Conclusions

Bipolar Disorder

• It is recognized, based on retrospective reports, that bipolar disorder often starts in the first two decades of life. While the disorder can be usually recognized during adolescence, it is, in many cases, difficult to formulate a definitive diagnosis in prepubertal years. Controversy exists among experts on how to interpret extreme volatility of mood, temper, and behavior in children. The presence of bipolar disorder in other biologically related members of the family is an important element to be considered in formulating a diagnosis of bipolar disorder in children.
• A proper and prompt diagnosis of bipolar disorder in children is important. If the disorder is not recognized, these children may be exposed to treatments with stimulants or antidepressants that may worsen the underlying mood disorder. On the other hand, an inaccurate diagnosis of bipolar can lead to unnecessary exposure to mood stabilizers, such as lithium and valproate, which can also cause side effects.
• A systematic, prospective, and extended evaluation of cohorts of children (including young children of preschool age) who are characterized by extreme mood changes can provide information on the clinical meaning of early mood lability and possible implications for later development of bipolar disorder.
• Little information is currently available on the efficacy and safety of the commonly used mood stabilizers in youths with bipolar disorder. Extrapolations of data from adult studies is in general not appropriate, especially with respect to safety data. Children may be more prone to certain side effects of medications than adults. Some data exist on the safety of valproate, which is commonly used for seizure control also in children. Still important unresolved questions remain about its possible role in inducing polycystic ovary syndrome in adolescent girls. Controlled studies are urgently needed in this area, with special emphasis on the long-term impact of these treatments on symptoms, disorder prognosis, physical and cognitive development.

Schizophrenia

• The diagnosis of schizophrenia is seldom made in prepubertal years. In part, this is due to the current uncertainty in interpreting symptoms of abnormal cognitive and behavioral functioning at this age. Systematic study and follow-up of multidimensionally impaired children may help identify valid precursors and prodromic signs of schizophrenia.
• A few studies on youths with prodromic signs of psychosis are in progress. This research is extremely interesting and promises to shed some light on the therapeutic value of very early treatment interventions.
• Important ethical issues must be addressed in considering, planning and conducting early treatment research in the prodrome of schizophrenia. A distinction must be clearly made between treatment of existing symptoms that are accompanied by clinical dysfunction and preventive interventions for subjects currently at risk but not clinically impaired.
• No adequate information exists on the efficacy and safety of antipsychotic medications prescribed to youths with schizophrenia and other psychotic disorders. This dearth is particularly evident for the atypical antipsychotics. Extrapolations of data from adult studies is in general not appropriate, especially with respect to safety data. Children may be more prone to certain medication side effects than adults. Controlled studies are urgently needed in this area, with special emphasis on the long-term impact of these treatments on symptoms, disorder prognosis, cognitive functions and development.

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