title: Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals: study protocol for a randomised controlled trial.
abstract: BACKGROUND
  Deviation from the physiological glucocorticoid dynamics (circadian and underlying ultradian rhythmicity) is a common characteristic of various neuropsychiatric and endocrine disorders as well as glucocorticoid-based therapeutics. These states may be accompanied by neuropsychiatric symptomatology, suggesting continuous dynamic glucocorticoid equilibrium is essential for brain homeostasis.
  
  
  METHODS
  The study consists of two parts. The preliminary stage of the study aims to validate (technically and pharmacologically) and optimise three different patterns of systemic cortisol administration in man. These patterns are based on the combinatory administration of metyrapone, to suppress endogenous cortisol production, and concurrent hydrocortisone replacement. The second, subsequent, core part of the study is a randomised, double-blinded, placebo-controlled, crossover study, where participants (healthy male individuals aged 18-60 years) will undergo all three hydrocortisone replacement schemes. During these infusion regimes, we plan a number of neurobehavioural tests and imaging of the brain to assess neural processing, emotional reactivity and perception, mood and self-perceived well-being. The psychological tests include: ecological momentary assessment, P1vital Oxford Emotional Test Battery and Emotional Potentiated Startle Test, Leeds Sleep Evaluation Questionnaire and the visual working memory task (n-back). The neuroimaging protocol combines magnetic resonance sequences that capture data related to the functional and perfusion status of the brain.
  
  
  CONCLUSIONS
  Results of this clinical trial are designed to evaluate the impact (with possible mechanistic insights) of different patterns of daily glucocorticoid dynamics on neural processing and reactivity related to emotional perception and mood. This evidence should contribute to the optimisation of the clinical application of glucocorticoid-based therapeutics.
  
  
  BACKGROUND
  UK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013).
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK. kk13382@bristol.ac.uk.|Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, BS28HW, UK. kk13382@bristol.ac.uk.|Clinical Research and Imaging Centre, University of Bristol, Bristol, BS28DX, UK. kk13382@bristol.ac.uk.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kalafatakis
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK. georgina.russell@bristol.ac.uk.|Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, BS28HW, UK. georgina.russell@bristol.ac.uk.
authors.forename: Georgina M
authors.initials: GM
authors.lastname: Russell
authors.affiliation: Department of Psychiatry, Medical Sciences Division, University of Oxford, Oxford, OX37JX, UK. catherine.harmer@psych.ox.ac.uk.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Harmer
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, BS81TU, UK. marcus.munafo@bristol.ac.uk.
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Munafo
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK. nicky.marchant@bristol.ac.uk.|Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, BS28HW, UK. nicky.marchant@bristol.ac.uk.
authors.forename: Nicky
authors.initials: N
authors.lastname: Marchant
authors.affiliation: Clinical Research and Imaging Centre, University of Bristol, Bristol, BS28DX, UK. aileen.wilson@bristol.ac.uk.
authors.forename: Aileen
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Clinical Research and Imaging Centre, University of Bristol, Bristol, BS28DX, UK. jon.brooks@bristol.ac.uk.
authors.forename: Jonathan C W
authors.initials: JC
authors.lastname: Brooks
authors.affiliation: Clinical Research and Imaging Centre, University of Bristol, Bristol, BS28DX, UK. jade.thai@bristol.ac.uk.
authors.forename: Ngoc J
authors.initials: NJ
authors.lastname: Thai
authors.affiliation: School of Medicine, University of Tasmania, Hobart, TAS 7000, Australia. stuart.ferguson@utas.edu.au.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Ferguson
authors.affiliation: Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, BS28HW, UK. kirsty.stevenson@uhbristol.nhs.uk.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Stevenson
authors.affiliation: Clinical Research and Imaging Centre, University of Bristol, Bristol, BS28DX, UK. claire.durant@bristol.ac.uk.
authors.forename: Claire
authors.initials: C
authors.lastname: Durant
authors.affiliation: Department of Psychiatry, Medical Sciences Division, University of Oxford, Oxford, OX37JX, UK. kristin.schmidt@psych.ox.ac.uk.
authors.forename: Kristin
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK. stafford.lightman@bristol.ac.uk.|Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, BS28HW, UK. stafford.lightman@bristol.ac.uk.
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002985:Clinical Protocols; D018592:Cross-Over Studies; D004644:Emotions / Q000187:drug effects*; D020249:Hormone Replacement Therapy; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging
chemical_list: D006854:Hydrocortisone