Abstract
BackgroundDeviation 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/designThe 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.DiscussionResults 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.Trial registrationUK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013)
Highlights
Deviation from the physiological glucocorticoid dynamics is a common characteristic of various neuropsychiatric and endocrine disorders as well as glucocorticoid-based therapeutics
Results of this clinical trial are designed to evaluate the impact 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
Summary
This project aims to investigate the impact of dynamic changes in glucocorticoid rhythmicity on neural processing of emotional perception as well as cognitive and behavioural phenotypes in healthy male individuals, utilising functional imaging of the brain and a series of cognitive and psychological tests. Based on the above criteria, we have derived the ideal metyrapone treatment dose for study days 4 and 5 as: 0.75 g during breakfast (day 4), 0.75 g during lunch (day 4) and 1 g before going to sleep at night (day 4) and 0.75 g during breakfast (day 5) This treatment strategy effectively suppresses endogenous adrenal activity in a reversible manner and results in plasma cortisol profiles that reliably reflect the pattern of exogenous hydrocortisone administration. This study aims to shed light on the impact of different patterns of daily glucocorticoid dynamics on neural processing, emotional reactivity and perception, mood and self-perceived well-being For this purpose, the study adopts an interventional approach based on per os metyrapone treatment, suppressing in a safe manner endogenous cortisol production, coupled with three alternative patterns of exogenous hydrocortisone replacement. All authors contributed to the writing of the manuscript and approved the final version
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