Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic–pituitary–adrenal-axis dysregulation: a study protocol description
Creators: name: de Nooij, Laura
name: Wirz, Lisa
name: Heling, Emma
name: Pais, Mariana
name: Hendriks, Gert-Jan
name: Verkes, Robbert-Jan
name: Roozendaal, Benno
name: Hermans, Erno J.
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Neuroscience
subject: Physiology
subject: FOS: Biological sciences
subject: Biological Sciences not elsewhere classified
subject: Science Policy
subject: Mental Health

description: <b>Background:</b> Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients – potentially with substantial exposure to early-life adversity (ELA) – show dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories. <b>Objective:</b> We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration. <b>Method:</b> The observational study (<i>n </i>= 160 PTSD group, <i>n </i>= 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (<i>n </i>= 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts. <b>Conclusion:</b> The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies. <b>Trial registration:</b> The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30. This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit. This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment. The study examines whether glucocorticoids enhance the strength and generalization of extinction memory. A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.