title: The developmental trajectory of bipolar disorder.
abstract: BACKGROUND
  Bipolar disorder is highly heritable and therefore longitudinal observation of children of affected parents is important to mapping the early natural history.
  
  
  OBJECTIVE
  To model the developmental trajectory of bipolar disorder based on the latest findings from an ongoing prospective study of the offspring of parents with well-characterised bipolar disorder.
  
  
  METHODS
  A total of 229 offspring from families in which 1 parent had confirmed bipolar disorder and 86 control offspring were prospectively studied for up to 16 years. High-risk offspring were divided into subgroups based on the parental long-term response to lithium. Offspring were clinically assessed and DSM-IV diagnoses determined on masked consensus review using best estimate procedure. Adjusted survival analysis and generalised estimating equations were used to calculate differences in lifetime psychopathology. Multistate models were used to examine the progression through proposed clinical stages.
  
  
  RESULTS
  High-risk offspring had an increased lifetime risk of a broad spectrum of disorders including bipolar disorder (hazard ratio (HR) = 20.89; P = 0.04), major depressive disorder (HR = 17.16; P = 0.004), anxiety (HR = 2.20; P = 0.03), sleep (HR = 28.21; P = 0.02) and substance use disorders (HR = 2.60; P = 0.05) compared with controls. However, only offspring from lithium non-responsive parents developed psychotic disorders. Childhood anxiety disorder predicted an increased risk of major mood disorder and evidence supported a progressive transition through clinical stages, from non-specific psychopathology to depressive and then manic or psychotic episodes.
  
  
  CONCLUSIONS
  Findings underscore the importance of a developmental approach in conjunction with an appreciation of familial risk to facilitate earlier accurate diagnosis in symptomatic youth.
authors.affiliation: Anne Duffy, MSc, MD, FRCPC Hotchkiss Brain Institute, Department of Psychiatry, University of Calgary, Alberta; Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia; and Mood Disorders Centre of Ottawa, Ontario; Julie Horrocks, PhD, Department of Mathematics & Statistics, University of Guelph, Ontario; Sarah Doucette, MSc, Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia; Charles Keown-Stoneman, MSc, Department of Mathematics & Statistics, University of Guelph, Ontario; Shannon McCloskey, MEd, Mood Disorders Centre of Ottawa, Ontario; Paul Grof, MD, PhD, FRCPC, Mood Disorders Centre of Ottawa, Ontario, and Department of Psychiatry, University of Toronto, Ontario, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Duffy
authors.forename: Julie
authors.initials: J
authors.lastname: Horrocks
authors.forename: Sarah
authors.initials: S
authors.lastname: Doucette
authors.forename: Charles
authors.initials: C
authors.lastname: Keown-Stoneman
authors.forename: Shannon
authors.initials: S
authors.lastname: McCloskey
authors.forename: Paul
authors.initials: P
authors.lastname: Grof
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics; D002648:Child; D016241:Child of Impaired Parents / Q000523:psychology / Q000706:statistics & numerical data*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D001523:Mental Disorders / Q000453:epidemiology* / Q000235:genetics; D010290:Parents / Q000523:psychology; D012893:Sleep Wake Disorders / Q000453:epidemiology / Q000235:genetics; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds