The Development and Application of the Prednisolone Suppression Test in Psychiatry: A Novel Tool for Assessing Glucocorticoid and Mineralocorticoid Receptor Function

Review Article

The Development and Application of the Prednisolone Suppression Test in Psychiatry: A Novel Tool for Assessing Glucocorticoid and Mineralocorticoid Receptor Function

Mario F Juruena ^{1 2 4 5}, Carmine M Pariante ^{2 3}, Andrew Papadopoulos ^{1 4} and Anthony J Cleare ^{1 3 4}

Affiliations: ¹Section of Neurobiology of Mood Disorders; ²Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology, Institute of Psychiatry, King’s College London, London, UK; ³NIHR Biomedical Research Centre at South London and Maudsley NHS Trust and Institute of Psychiatry (King’s College London); ⁴Affective Disorders Unit Laboratory, National Affective Disorders Unit, South London and Maudsley NHS Trust, London and ⁵Stress and Affective Disorders Program, Department of Neuroscience and Behaviour, University of Sao Paulo, Ribeirao Preto, Brazil


ABSTRACT

Glucocorticoids mediate their actions, including feedback regulation of the hypothalamic–pituitary–adrenal (HPA) axis, through two distinct corticosteroid receptor subtypes: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Dexamethasone, specifically the dexamethasone suppression test (DST), was the first and most studied glucocorticoid for assessing HPA axis activity; unfortunately, it has pharmacodynamic and pharmacokinetic features that are very distinct from cortisol. We have developed a novel suppressive test using prednisolone, which is pharmacologically more similar to cortisol than dexamethasone and can therefore obtain a more physiological assessment of HPA axis regulation. We describe here the development of the Prednisolone Suppression Test (PST), summarizing the preclinical work, studies in healthy control subjects, and applications to date in clinical populations. We propose that prednisolone at the 5‐mg dosage, together with the assessment of salivary cortisol, can be used to investigate both impaired and enhanced glucocorticoid‐mediated negative feedback. The work undertaken to date suggests that, in major depression, results using the PST differ from those of the DST, in that patients who are non‐suppressors to dexamethasone show normal suppressive responses to prednisolone. Furthermore, preserved suppressive responses to prednisolone predict treatment response in previously difficult‐to‐treat depression, whereas prednisolone non‐suppression is predictive of severe treatment resistance even to the most intensive treatments. In another group of patients—chronic fatigue syndrome—data to date suggest that there is enhanced sensitivity of the HPA axis to negative feedback demonstrable using the PST. We argue that the different results using the PST, which probes both MR and GR, and the DST, which probes only GR, suggest a dissociation between GR and MR function in subgroups of patients. Although still primarily a research tool to aid understanding of the relevance of HPA axis dysfunction in psychiatric disorders, the ability to distinguish “true” from “pseudo” treatment‐resistant depression suggests that the PST holds promise as a potential clinical tool.

Keywords: cortisol, depression, glucocorticoid receptor, hypothalamic–pituitary–adrenal (HPA) axis, mineralocorticoid receptor,prednisolone, treatment-resistant depression
Correspondence: Mario F. Juruena, Stress and Affective Disorders Program, Department of Neuroscience and Behaviour, University of Sao
Paulo, Tenente Catao Roxo, 2650, R. Preto-SP, 14051-140, Brazil. e-mail: juruena@fmrp.usp.br