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/design: 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.

Discussion: 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.

Trial registration: UK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013).

Fig. 1

Main steps followed in recruiting and working with volunteers during study stage 1. Interested participants were phone screened, and if screening was positive, an initial appointment was scheduled to discuss in full detail the parameters of the study and answer any queries. During that appointment, a full screening process takes place. If participants are still eligible and willing to participate, signed informed consent is obtained. A date to conduct the five-day interventional study (metyrapone and hydrocortisone administration) is then arranged. The 24-hour study is performed after midday (around 2:00–3:00 pm) of day 4 until after midday (around 2:00–3:00 pm) of day 5. HABS: human automated blood sampler

Fig. 2

Main steps followed in recruiting and working with volunteers during study stage 2. Interested participants are phone screened, and if screening positive, an initial appointment is scheduled to discuss in full detail the parameters of the study and answer any queries. During that appointment, a detailed screening process would take place. If participants are still eligible and willing to participate, signed informed consent is obtained. Additionally, as part of the screening process, participants need to give a urine sample to test for drugs of abuse and undergo an initial anatomical magnetic resonance (MR) scan. If still eligible, the dates for the conduction of the three study arms are arranged. The order of treatment arm allocation is random and unknown to the volunteers and the study investigators. This is determined by an external authority and takes place prior to the start of arm 1. Interventions during the three study arms were designed and validated during the previous study stage. Each of the three arms takes place with a temporal distance from the previous one of at least two weeks (*). EMA: ecological momentary assessment, ETB: emotional test battery, EPST: emotion potentiated startle test, LD: last study day, LSEQ: Leeds Sleep Evaluation Questionnaire, MRI: magnetic resonance imaging, RAP: randomisation phase, WP: wash-out period

Fig. 3

Tasks of controlled block design used during the functional neuroimaging protocol. a During the implicit facial expression processing task, individuals are exposed to alternating visual stimuli (pictures) consisting of 30-second blocks of human faces with a particular facial expression (fear -F- or happiness -H- or sadness -S). Each block corresponds to one kind of facial expression, where 10 different human faces, male or female, with the same facial expression are presented for 0.1 second with a 2.9-second inter-stimulus interval. Blocks are divided from each other by resting state periods (lasting 30 seconds). Each kind of block (F, H, S) is repeated four times. The paradigm starts and finishes with a resting state period. Participants are given a button box and explicitly instructed to press a corresponding button depending on whether the face they see each time is male or female (gender discrimination). Both accuracy and response time are recorded. b During the flashing checkerboard task, individuals are visually exposed to a flashing checkerboard (a checkerboard whose cells alternate between white and black colours with a frequency of 7.5 Hz) for 16 seconds followed by a resting period of 15 seconds before the next flashing checkerboard visual stimulation initiates. The resting period-flashing checkerboard alternation is repeated 10 times. Subjects are instructed to have their eyes open and look at the screen all the time

Fig. 4

Systemic 24-hour cortisol profiles of three individuals participating in study stage 1. All participants were under the combined treatment of metyrapone and hydrocortisone per os. The pattern of oral hydrocortisone administration is presented in Table 3, and was identical in all three participants. Metyrapone treatment differed between the three individuals as indicated in the corresponding small tables within the figure; for each small table, each column represents a study day and each row represents the time point within the day in chronological order (during breakfast, lunch and in the evening) to receive metyrapone. The numbers within the small tables’ cells represent the number of metyrapone pills administered (1 pill = 250 mg metyrapone). Circulating cortisol levels in participant A exceeded normal values at all periods of his 24-hour study, while during his sleep period cortisol pulses were present (red part of the curve) which could not be explained by substitution therapy. Thus, adrenal gland suppression was ineffective. For participant B, the evening dose at every study day was transferred from dinner time to just prior to going to sleep for the night, and a number of doses during study days 3, 4 and 5 were increased from 2 to 3 pills, as indicated in red colour in corresponding small table. Circulating cortisol levels in participant B remained under normal values at all periods of his 24-hour study except for the morning peak and some signs of endogenous adrenal activity just prior to awaking (red part of the curve). For participant C, the evening dose of study day 4 was further increased from 3 to 4 pills as indicated in red colour in corresponding small table. Based on the biochemical results of participant C, this last metyrapone treatment scheme was adapted as the ideal one to effectively suppress adrenal gland for the exogenous hydrocortisone administration to reliably define the exogenously derived pattern of circulating cortisol dynamics

Fig. 5

Optimised metyrapone treatment and subcutaneously continuous hydrocortisone replacement. Plasma 24-hour cortisol and corticotrophin (ACTH) profiles of one individual participating in study stage 1. The subject received the optimal metyrapone (Fig. 4, participant C) along with hydrocortisone substitution therapy, subcutaneously (SC), in a continuous manner via Animas® Vibe™ Insulin Pump. The pattern of continuous SC hydrocortisone administration is presented in Table 3; between 08:00 pm–02:00 am the flow rate of hydrocortisone substitution is 0.1 mg/h, followed by an increase to 2 mg/h between 02:00–08:00 am, to drop to 1 mg/h between 08:00 am–12:00 pm, followed by a further decline to 0.4 mg/h between 12:00–08:00 pm. (Total daily dose adds up to 19.8 mg/day.) The black arrows indicate the time points of shifting from one flow rate to the next. Due to technical problems, blood samples of the first 5 hours of the study could not be analysed. This mode of hydrocortisone replacement tries to mimic the normal circadian profile (daily cortisol levels rise in the early morning hours reaching their peak around 08:00 am, near 500 nmol/L before starting to fall throughout the rest of the day to reach their trough around 02:00 am of the next day, near 50 nmol/L) but without the physiologically underlying ultradian rhythm. ACTH fluctuations within normal values confirm the physiological state of the hypothalamic-pituitary-adrenal axis.

Fig. 6

Optimised metyrapone treatment and subcutaneously pulsatile hydrocortisone replacement. Plasma 24-hour cortisol and corticotrophin (ACTH) profiles of one individual participating in study stage 1. The subject received the optimal metyrapone (Fig. 4, participant C) along with hydrocortisone substitution therapy, subcutaneously (SC), in a pulsatile manner via Crono P® pump (CANE Applied Medical Technology Ltd, Cambridge, UK). The pattern of pulsatile SC hydrocortisone administration is presented in Table 3; pulses are also indicated as black arrows in the figure. Corresponding dose of hydrocortisone is indicated above each arrow (adding up to 19.9 mg/day). This mode of hydrocortisone replacement tries to approximate the physiological (normal circadian and underlying ultradian) profile of endogenous cortisol secretion. ACTH fluctuations within normal values confirm the physiological state of the hypothalamic-pituitary-adrenal axis