title: Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder.
abstract: BACKGROUND
  Impaired stress resilience and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients.
  
  
  METHODS
  Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR).
  
  
  RESULTS
  Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels.
  
  
  CONCLUSIONS
  Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness.
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg). gabrielrfries@gmail.com.
authors.forename: Gabriel Rodrigo
authors.initials: GR
authors.lastname: Fries
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Mirela Paiva
authors.initials: MP
authors.lastname: Vasconcelos-Moreno
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Carolina
authors.initials: C
authors.lastname: Gubert
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Bárbara Tietböhl Martins Quadros
authors.initials: BT
authors.lastname: dos Santos
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Juliana
authors.initials: J
authors.lastname: Sartori
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Bárbara
authors.initials: B
authors.lastname: Eisele
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Pamela
authors.initials: P
authors.lastname: Ferrari
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Adam
authors.initials: A
authors.lastname: Fijtman
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rüegg
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Nils Christian
authors.initials: NC
authors.lastname: Gassen
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Flávio
authors.initials: F
authors.lastname: Kapczinski
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.affiliation: INCT for Translational Medicine, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (Drs Fries, Vasconcelos-Moreno, Gubert, dos Santos, Sartori, Eisele, Ferrari, Fijtman, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Porto Alegre, Brazil (Drs Fries, Gubert, Kapczinski, and Kauer-Sant'Anna); Programa de Pós-Graduação em Ciências Médicas: Psiquiatria, UFRGS, Porto Alegre, Brazil (Drs Vasconcelos-Moreno, Ferrari, Kapczinski, and Kauer-Sant'Anna); Max Planck Institute of Psychiatry, Munich, Germany (Drs Gassen and Rein); Karolinska Institute, Stockholm, Sweden (Dr Rüegg).
authors.forename: Márcia
authors.initials: M
authors.lastname: Kauer-Sant'Anna
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008745:Methylation; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012463:Saliva / Q000378:metabolism; D035781:Siblings; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000324:Adrenocorticotropic Hormone; D003907:Dexamethasone; D005938:Glucocorticoids; D006854:Hydrocortisone; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: FKBP51; HPA axis.; bipolar disorder; cortisol; glucocorticoid receptor