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. 2014 Oct 31;18(1):pyu043.
doi: 10.1093/ijnp/pyu043.

Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder

Gabriel Rodrigo Fries  1 , Mirela Paiva Vasconcelos-Moreno  2 , Carolina Gubert  2 , Bárbara Tietböhl Martins Quadros dos Santos  2 , Juliana Sartori  2 , Bárbara Eisele  2 , Pamela Ferrari  2 , Adam Fijtman  2 , Joëlle Rüegg  2 , Nils Christian Gassen  2 , Flávio Kapczinski  2 , Theo Rein  2 , Márcia Kauer-Sant'Anna  2
Affiliations

Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder

Gabriel Rodrigo Fries et al. Int J Neuropsychopharmacol. .

Erratum in

  • Erratum.
    [No authors listed] [No authors listed] Int J Neuropsychopharmacol. 2016 Apr 27;19(10):pyw031. doi: 10.1093/ijnp/pyw031. Int J Neuropsychopharmacol. 2016. PMID: 27207904 Free PMC article. No abstract available.

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.

Keywords: FKBP51; HPA axis.; bipolar disorder; cortisol; glucocorticoid receptor.

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Figures

Figure 1.
Figure 1.
HPA axis activity and FKBP51 alterations in bipolar disorder. (A) Post-dexamethasone salivary cortisol levels; one-way ANOVA followed by Tukey’s post hoc test. (B) Ex vivo GR responsiveness assay. Isolated peripheral blood mononuclear cells were incubated with increasing concentrations of dexamethasone, with assessment of FKBP5 mRNA levels after 24 hours; Kruskall-Wallis followed by Mann-Whitney test and Bonferroni correction. (C) Basal FKBP5 mRNA levels; one-way ANOVA followed by Tukey’s post hoc test. (D) FKBP51 protein levels; Kruskall-Wallis followed by Mann-Whitney test and Bonferroni correction. (E–F) Methylation status of the FKBP5 gene at two specific CpG dinucleotides; one-way ANOVA followed by Tukey’s post hoc test. *p = 0.008 (BD patients vs. controls). RQ: relative quantification.
Figure 2.
Figure 2.
HPA axis activity and FKBP51 alterations in patients with early- vs. late-stage bipolar disorder. (A) Post-dexamethasone salivary cortisol levels; one-way ANOVA followed by Tukey’s post hoc test. (B) Ex vivo GR responsiveness assay; Kruskall-Wallis followed by Mann-Whitney test and Bonferroni correction. (C) Basal FKBP5 mRNA levels; Kruskall-Wallis followed by Mann-Whitney test and Bonferroni correction. (D) FKBP51 protein levels; Kruskall-Wallis followed by Mann-Whitney test and Bonferroni correction. (E–F) Methylation status of the FKBP5 gene at two specific CpG dinucleotides; one-way ANOVA followed by Tukey’s post hoc test. BD: bipolar disorder.
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