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Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder.

ABSTRACT: Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and increases the release of hypothalamic CRF and pituitary adrenocorticotropic hormone (ACTH). Laboratory-based polysomnography was used to monitor the sleep of 66 medically healthy, medication-free men and pre-menopausal follicular phase women including 33 with chronic PTSD (16 women and 17 men) and 33 age- and sex-matched controls (14 women and 19 men) over 3 consecutive nights. Participants completed an overnight metyrapone challenge after an adaptation and baseline night of sleep and ACTH was obtained by repeated blood sampling. Metyrapone resulted in a greater increase in ACTH and greater decreases in cortisol and delta spectral power sleep in PTSD subjects compared to controls, and a greater increase in ACTH in women compared to men. There was no sex difference in metyrapone effects on delta power sleep, and no significant metyrapone by PTSD by sex interactions with either ACTH or delta power sleep. Regression analyses indicated that a greater increase in ACTH response was associated with a greater decrease in delta power sleep response in PTSD subjects, but no such relationship was found in controls. The PTSD group difference was similar in men and women. These results suggest that stress-related alterations of the HPA axis in PTSD may contribute to sleep difficulties. Therapeutics that target the HPA axis may offer promise as a potential future treatment for PTSD and related sleep difficulties.

SUBMITTER: Inslicht SS

PROVIDER: S-EPMC6170159 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder.

Inslicht Sabra S SS Rao Madhu N MN Richards Anne A O'Donovan Aoife A Gibson Carolyn J CJ Baum Tierney T Metzler Thomas J TJ Neylan Thomas C TC

Psychoneuroendocrinology 20171207

Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and inc ...[more]

PMID: 29268182

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Project description:BackgroundSexual assault is implicated in several adverse psychological and physical health outcomes, including posttraumatic stress disorder (PTSD) and depression. Neurobiological research has shown variations related to the hypothalamic-pituitary-adrenal (HPA) axis, immune alterations, metabolic function, and brain circuitry. Although these mechanisms have been extensively studied, the results have demonstrated different outcomes in PTSD.MethodsWe compared the plasma adrenocorticotropin (ACTH) and salivary cortisol levels of fifty-eight women with PTSD developed after sexual assault to those of forty-four female controls with no history of trauma. We also evaluated the psychiatric diagnosis and symptom severity of PTSD and depression. The participants' clinical conditions were associated with their hormonal levels to assess whether symptom severity was related to hormonal imbalance.ResultsA large percentage of sexually assaulted women had PTSD and comorbid depression. The ACTH levels were higher in the PTSD group than the control group and increased as PTSD severity increased, considering depressive symptoms, measured by the Beck Depression Inventory (BDI) (p < 0.0001), as well as PTSD symptoms, measured by subscale D of the Clinician-Administered PTSD Scale (CAPS-5) (p = 0.045) and the CAPS-5 total scale (p = 0.026). Cortisol levels measured at 10 pm were higher for the PTSD group than the control group (p = 0.045, p = 0.037, respectively), and the cortisol awakening response showed elevated cortisol levels for the PTSD group.ConclusionsThese results show a correlation between symptom severity and HPA axis imbalance in patients with PTSD. Elevated ACTH and an elevated cortisol response in patients with comorbid depressive symptoms were the opposite of the expected response for patients with PTSD only. This association leads to the hypothesis that the neurobiological alterations of PTSD are related to the type of symptoms presented and their severity. These manifestations likely influence the disease course, prognosis and response to treatment. These outcomes highlight the need to discuss particular neurobiological alterations in patients with PTSD developed after sexual assault, mainly those with severe depressive symptoms.

Project description:Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar ("matching") adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA-axis hyper-reactivity in adulthood, as also found in major depression. This hyper-activity is related to increased corticotrophin-releasing hormone signaling and impaired glucocorticoid receptor-mediated negative feedback. In contrast, initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder, and future studies should investigate its neural/neuroendocrine foundation in further detail. Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.

Dataset Information

Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder.

Publications

Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder.

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