Disturbances in Hypothalamic-Pituitary-Adrenal Axis and Immunological Activity Differentiating between Unipolar and Bipolar Depressive Episodes

PLoS One. 2015 Jul 21;10(7):e0133898. doi: 10.1371/journal.pone.0133898. eCollection 2015.

Abstract

Introduction: Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients.

Methods: Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers.

Results: In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women.

Conclusion: Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity simultaneously, but more research is needed to unravel their interrelatedness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers / blood
  • Bipolar Disorder / blood*
  • C-Reactive Protein / metabolism
  • Depression / blood*
  • Female
  • Humans
  • Hydrocortisone / blood*
  • Hypothalamo-Hypophyseal System / metabolism*
  • Interleukin-6 / blood
  • Male
  • Middle Aged
  • Pituitary-Adrenal System / metabolism*
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Biomarkers
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • C-Reactive Protein
  • Hydrocortisone

Grants and funding

The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Health Care (IQ Healthcare), Netherlands Institute for Health Services Research (Nivel) and the Netherlands Institute of Mental Health and Addiction (TRIMBOS)). Assaying of inflammatory markers was supported by the Neuroscience Campus Amsterdam and VIDI grant (Penninx). Statistical analyses were supported by an unrestricted research grant by Astra Zeneca Nederland (Spijker, Hoencamp, Boschloo). The Netherlands Organization for Health Research and Development had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. PsyQ Rijnmond provided support in the form of salaries for authors AS and EH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Astra Zeneca Nederland had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.