Adolescents at High Risk for Familial Bipolar Disorder / NIMH Study 55


Study 55 Description

Study 55 was funded through the NIMH grant R01 MH068009 entitled "Adolescents at High Risk for Familial Bipolar Disorder".  Principal investigator was John I. Nurnberger, Jr., M.D., Ph.D., Indiana University.

Bipolar disorder (BP) is a highly heritable disorder with up to 85% of variance in risk determined by genetic factors.  Family history remains the strongest predictive factor for development of the disorder.  Studies of late adolescent and young adult offspring of parents with BP clearly show an increased onset of major affective disorders, including recurrent major depression, BP type I (BPI), and BPII.  Adolescent offspring in families of probands with BP (the intially indentified subject in a family/genetic study) are at 8- to 10-fold increased lifetime risk for BP and at 3-fold increased lifetime risk for major affective disorders in general.

Studies of offspring of probands with BP have typically found a general increase in psychiatric diagnoses in childhood.  It is unclear to what extent this increase in diagnoses is an indicator of risk of later mood disorder and to what extent it reflects the stress of living with an affected parent or other familial factors.

Studies involving high-risk subgroups have the distinct advantage of engaging study subjects prior to the onset of the disorder; they offer the ability to prospectively detail the emerging psychopathologic condition and provide for comparison between at-risk offspring who become affected and those who do not become affected.  Longitudinal studies that ascertain at-risk participants and monitor them prospectively are the most effective approach for identifying specific etiologic factors.  The present study uses best-estimate diagnoses for childhood disorders as well as adolescent/young adult mood disorder; we also investigated the time course of disorder onset.

We identified at-risk offspring from cohorts specifically selected for genetic study.  Cases and controls were compared for lifetime diagnoses; we then characterized subtypes of case offspring at increased risk for major affective disorders.  We hypothesized that early internalizing disorders and externalizing disorders (or both) would predict the onset of major affective disorders in families affected by bipolar illness.  The advantage of the study design is that it identifies subphenotypes and allows incorporation of cohort-specific genetic risk markers as the study progresses.  All the clinical procedures were approved by institutional review boards at the 4 subject collection sites: Indiana University School of Medicine, Indianapolis (coordinating site); University of Michigan, Ann Arbor; The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Washington University at St. Louis, St. Louis, Missouri.  Informed consent (or assent with parental consent for subjects <18 years old) was obtained after a thorough explanation of the study.  "Case" offspring (the term as used herein does not connote illness but rather "at-risk" status) were ascertained through probands with BP, available from the National Institute of Mental Health Genetics Initiative bipolar sample ( or similar genetic studies.  To our knowledge, all the probands were in treatment at the time of ascertainment (approximately 95% in out patient treatment and 5% in inpatient treatment).  Probands were characterized using the Diagnostic Interview for Genetic Studies and the Family Instrument for Genetics Studies and had a lifetime DSM-IV diagnosis of BPI, BPII with recurrent major depression, or schizoaffective disorder, bipolar type.  Second-degree relatives were included only when the family was multiplex (at least a proband with BPI and a first-degree relative of the proband with BPI/schizoaffective disorder, bipolar type); multiplex families are associated with a generally higher risk of illness in relatives.  Control parents were recruited through general medicine clinics, motor vehicle records, and campus advertising.  Exclusion criteria for control parents included BPI, BPII, recurrent major depression, schizoaffective disorder, or schizophrenia in either parent; we also excluded parents with a first-degree relative with a psychiatric hospitalization1.

Acknowledgement:  Data and biomaterials were collected in four projects that participated in the Adolescents at High Risk for Familial Bipolar Disorder funded by NIMH.  From 2004-2009, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01MH068009, John I. Nurnberger, Jr., M.D., Ph.D., Robert Schweitzer, M.D., Gina Laite, M.D., Kelly Rhoadarmer, M.D., Vegas Coleman, M.D., Elliot S. Gershon, M.D.; University of Chicago, Wade Berrettini, M.D., Ph.D.; University of Pennsyvania, Carrie Fisher, R.N., Mariano Erpe, M.S.; University of Michigan, Ann Arbor, MI, R01MH068006, Melvin McInnis, M.D., Masoud Kamali, M.D., Christine Brucksch, R.N.; Johns Hopkins University, Baltimore, MD, R01MH068006, Elizabeth Kastelic, M.D., Holly C. Wilcox, Ph.D.; Washington University, St. Louis, MO, R01MH073151, Wendy Reich, Ph.D., Anne Glowinski, M.D., M.P.E., Julia Morgan, M.A., Caroline Drain, M.H.S.

1Reference:  Nurnberger JI Jr, McInnis M, Reich W, Kastelic E, Wilcox HC, Glowinski A, Mitchell P, Fisher C, Erpe M, Gershon ES, Berrettini W, Laite G, Schweitzer R, Rhoadarmer K, Coleman VV, Cai X, Azzouz F, Liu H, Kamali M, Brucksch C, Monahan PO.  A high-risk study of bipolar disorder. Childhood clinical phenotypes as precursor of major mood disorders.  Arch Gen Psychiatry 2011 Oct; 68(10):1012-1020.  PMID: 21969459

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