title: Illness progression as a function of independent and accumulating poor prognosis factors in outpatients with bipolar disorder in the United States.
abstract: OBJECTIVE
  Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression.
  
  
  METHODS
  From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, χ(2), and logistical regression.
  
  
  RESULTS
  All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course.
  
  
  CONCLUSIONS
  Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder.
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Post
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Lori L
authors.initials: LL
authors.lastname: Altshuler
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Leverich
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Willem A
authors.initials: WA
authors.lastname: Nolen
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Ralph
authors.initials: R
authors.lastname: Kupka
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Heinz
authors.initials: H
authors.lastname: Grunze
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Trisha
authors.initials: T
authors.lastname: Suppes
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Susan L
authors.initials: SL
authors.lastname: McElroy
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Paul E
authors.initials: PE
authors.lastname: Keck
authors.affiliation: Bipolar Collaborative Network, Bethesda, Maryland (Drs Post and Rowe and Mr Leverich); UCLA Mood Disorders Research Program and VA Medical Center, Los Angeles (Dr Altshuler); Universitair Medisch Centrum Groningen (UMCG), Groningen, The Netherlands (Dr Nolen); Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands (Dr Kupka); Newcastle University, Institute of Neuroscience, Newcastle upon Tyne, United Kingdom (Mr Grunze); Department of Psychiatry, Mayo Clinic, Rochester, Minnesota (Dr Frye); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto and VA Palo Alto Health Care System, Palo Alto, California (Dr Suppes); Lindner Center of HOPE, Mason, Ohio and Biological Psychiatry Program, University of Cincinnati Medical College, Cincinnati, Ohio (Dr McElroy); and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio and Lindner Center of HOPE, Mason, Ohio (Dr Keck).
authors.forename: Mike
authors.initials: M
authors.lastname: Rowe
references.citation: J Psychiatr Res. 2009 Apr;43(7):680-6
references.pmid: 19000625
references.citation: Ann N Y Acad Sci. 2006 Dec;1094:235-47
references.pmid: 17347355
references.citation: Br J Psychiatry. 2008 Feb;192(2):150-1
references.pmid: 18245035
references.citation: Bipolar Disord. 2007 Nov;9(7):698-705
references.pmid: 17988359
references.citation: Science. 2003 Jul 18;301(5631):386-9
references.pmid: 12869766
references.citation: Arch Gen Psychiatry. 2008 Nov;65(11):1331-5
references.pmid: 18981345
references.citation: J Clin Psychiatry. 2003 May;64(5):506-15
references.pmid: 12755652
references.citation: J Affect Disord. 2014 May;160:27-33
references.pmid: 24709019
references.citation: World J Biol Psychiatry. 2014 Jul;15(5):369-76
references.pmid: 22188366
references.citation: Bipolar Disord. 2005 Aug;7(4):344-50
references.pmid: 16026487
references.citation: JAMA. 2005 Feb 23;293(8):956-63
references.pmid: 15728166
references.citation: Bipolar Disord. 2007 Aug;9(5):531-5
references.pmid: 17680925
references.citation: Prev Chronic Dis. 2006 Apr;3(2):A42
references.pmid: 16539783
references.citation: J Neurol Neurosurg Psychiatry. 2004 Dec;75(12):1662-6
references.pmid: 15548477
references.citation: Nat Neurosci. 2010 Nov;13(11):1313-8
references.pmid: 20975754
references.citation: Nat Rev Neurosci. 2007 May;8(5):355-67
references.pmid: 17453016
references.citation: J Affect Disord. 1998 Nov;51(2):145-51
references.pmid: 10743847
references.citation: Br J Psychiatry Suppl. 2001 Jun;41:s169-76
references.pmid: 11450179
references.citation: Am J Psychiatry. 2005 Nov;162(11):2152-61
references.pmid: 16263857
references.citation: Am J Psychiatry. 2009 Jul;166(7):795-804
references.pmid: 19448190
references.citation: Biol Psychiatry. 2009 Mar 1;65(5):432-7
references.pmid: 18990366
references.citation: Br J Psychiatry. 2013 Mar;202(3):172-6
references.pmid: 23457180
references.citation: Psychiatry Res. 2013 Dec 30;210(3):880-6
references.pmid: 24021999
references.citation: J Clin Psychiatry. 2010 Sep;71(9):1176-86; quiz 1252-3
references.pmid: 20923622
references.citation: Acta Psychiatr Scand. 2013 Feb;127(2):136-44
references.pmid: 22901015
references.citation: Int Clin Psychopharmacol. 2011 Mar;26(2):96-106
references.pmid: 21178634
references.citation: J Psychiatr Res. 2003 Jul-Aug;37(4):297-303
references.pmid: 12765852
references.citation: Am J Psychiatry. 2007 Apr;164(4):582-90
references.pmid: 17403971
references.citation: Isr J Psychiatry Relat Sci. 2012;49(2):95-101
references.pmid: 22801288
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):E513-8
references.pmid: 21813766
references.citation: Bipolar Disord. 2012 Sep;14(6):641-53
references.pmid: 22938168
references.citation: Dialogues Clin Neurosci. 2011;13(1):25-39
references.pmid: 21485744
references.citation: J Psychiatr Res. 2011 Sep;45(9):1146-52
references.pmid: 21470621
references.citation: Transl Psychiatry. 2013 May 21;3:e261
references.pmid: 23695236
references.citation: Am J Psychiatry. 2006 Feb;163(2):240-6
references.pmid: 16449477
references.citation: J Am Acad Child Adolesc Psychiatry. 2013 Feb;52(2):121-31
references.pmid: 23357439
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17312-5
references.pmid: 15574496
references.citation: Am J Psychiatry. 1992 Aug;149(8):999-1010
references.pmid: 1353322
references.citation: Bipolar Disord. 2009 Jun;11(4):391-400
references.pmid: 19500092
references.citation: J Clin Psychiatry. 2012 Apr;73(4):e561-6
references.pmid: 22579163
references.citation: J Nerv Ment Dis. 2014 Apr;202(4):265-70
references.pmid: 24647213
references.citation: Arch Gen Psychiatry. 2009 Dec;66(12):1287-9
references.pmid: 19996033
references.citation: J Affect Disord. 2011 Dec;135(1-3):43-50
references.pmid: 21880373
references.citation: J Psychiatr Res. 2012 May;46(5):561-73
references.pmid: 22444599
references.citation: Psychiatr Serv. 2007 Jan;58(1):85-91
references.pmid: 17215417
references.citation: Arch Gen Psychiatry. 1992 Feb;49(2):126-31
references.pmid: 1550465
references.citation: Biol Psychiatry. 2002 Feb 15;51(4):288-97
references.pmid: 11958779
references.citation: Biol Psychiatry. 2004 May 1;55(9):875-81
references.pmid: 15110730
references.citation: J Affect Disord. 1989 Mar-Jun;16(2-3):167-79
references.pmid: 2522116
references.citation: J Am Acad Child Adolesc Psychiatry. 2000 Apr;39(4):453-60
references.pmid: 10761347
references.citation: Int Clin Psychopharmacol. 2011 Nov;26(6):323-8
references.pmid: 21876441
references.citation: J Clin Psychiatry. 2010 Jul;71(7):864-72
references.pmid: 20667291
references.citation: Bipolar Disord. 2007 Dec;9(8):828-38
references.pmid: 18076532
references.citation: Br J Psychiatry. 2013 Mar;202(3):212-9
references.pmid: 23349295
references.citation: Am J Psychiatry. 2005 Jul;162(7):1273-80
references.pmid: 15994709
references.citation: JAMA. 2009 Jun 17;301(23):2462-71
references.pmid: 19531786
references.citation: JAMA. 2007 Oct 17;298(15):1794-6
references.pmid: 17940236
references.citation: J Affect Disord. 1998 Jan;47(1-3):31-9
references.pmid: 9476741
references.citation: Arch Gen Psychiatry. 2007 May;64(5):543-52
references.pmid: 17485606
references.citation: Acta Psychiatr Scand. 2014 May;129(5):375-82
references.pmid: 24138298
references.citation: J Affect Disord. 2013 May;147(1-3):288-94
references.pmid: 23337654
references.citation: Am J Psychiatry. 2013 Jan;170(1):102-10
references.pmid: 23288387
references.citation: Am J Psychiatry. 2003 Jan;160(1):112-7
references.pmid: 12505809
references.citation: Nat Neurosci. 2009 Mar;12(3):342-8
references.pmid: 19234457
references.citation: Bipolar Disord. 2010 Mar;12(2):164-71
references.pmid: 20402709
references.citation: J Psychiatr Res. 2011 Oct;45(10):1273-82
references.pmid: 21683960
references.citation: Cell. 2007 Oct 19;131(2):391-404
references.pmid: 17956738
references.citation: Biol Psychiatry. 2000 Sep 15;48(6):477-85
references.pmid: 11018221
references.citation: Arch Gen Psychiatry. 2009 Mar;66(3):287-96
references.pmid: 19255378
references.citation: Arch Gen Psychiatry. 2011 Oct;68(10):1012-20
references.pmid: 21969459
references.citation: Biol Psychiatry. 2005 Oct 1;58(7):554-61
references.pmid: 16112654
references.citation: Am J Psychiatry. 2013 May;170(5):511-20
references.pmid: 23511308
references.citation: J Clin Psychiatry. 2012 Jul;73(7):924-30
references.pmid: 22480597
references.citation: J Am Acad Child Adolesc Psychiatry. 2005 Sep;44(9):846-71
references.pmid: 16113615
references.citation: Pediatrics. 2012 Jan;129(1):e232-46
references.pmid: 22201156
references.citation: J Am Acad Child Adolesc Psychiatry. 2004 Nov;43(11):1380-6
references.pmid: 15502597
references.citation: Am J Psychiatry. 2001 Apr;158(4):582-6
references.pmid: 11282692
references.citation: Bipolar Disord. 2012 Nov;14(7):780-9
references.pmid: 23107222
references.citation: Proc Natl Acad Sci U S A. 2013 May 14;110(20):8302-7
references.pmid: 23630272
references.citation: Biol Psychiatry. 2009 May 1;65(9):760-9
references.pmid: 19150054