Delta Sleep Response to Metyrapone in Post-Traumatic Stress Disorder

Abstract

Metyrapone blocks cortisol synthesis, which results in the stimulation of hypothalamic cortiocotropin-releasing factor (CRF) and a reduction in delta sleep. We examined the effect of metyrapone administration on endocrine and sleep measures in male subjects with and without chronic PTSD. We hypothesized that metyrapone would result in a decrease in delta sleep and that the magnitude of this decrease would be correlated with the endocrine response. Finally, we utilized the delta sleep response to metyrapone as an indirect measure of hypothalamic CRF activity and hypothesized that PTSD subjects would have decreased delta sleep at baseline and a greater decrease in delta sleep induced by metyrapone. Three nights of polysomnography were obtained in 24 male subjects with combatrelated PTSD and 18 male combat-exposed normal controls. On day 3, metyrapone was administered during normal waking hours until habitual sleep onset preceding night 3. Endocrine responses to metyrapone were measured in plasma obtained the morning following sleep recordings, the day before and after administration. Repeated measures ANOVAs were conducted to compare the endocrine and sleep response to metyrapone in PTSD and controls. PTSD subjects had significantly less delta sleep as indexed by stages 3 and 4, and total delta integrated amplitude prior to metyrapone administration. There were no differences in premetyrapone cortisol or ACTH levels in PTSD vs controls. PTSD subjects had a significantly decreased ACTH response to metyrapone compared to controls. Metyrapone caused an increase in awakenings and a marked decrease in quantitative measures of delta sleep that was significantly greater in controls compared to PTSD. The decline in delta sleep was significantly associated with the magnitude of increase in both 11-deoxycortisol and ACTH. The results suggest that the delta sleep response to metyrapone is a measure of the brain response to increases in hypothalamic CRF. These data also suggest that the ACTH and sleep EEG response to hypothalamic CRF is decreased in PTSD.

Hypothalamic–Pituitary–Adrenal Axis Activity and Sleep in Posttraumatic Stress Disorder

“…We have previously shown that PTSD subjects had a diminished adrenocorticotropin (ACTH) response and a less pronounced decrease of delta sleep to an indirect CRF challenge with metyrapone (Neylan et al, 2003). In that study, PTSD subjects had significantly less delta sleep, but no significant differences in total sleep time, sleep maintenance, REM latency, or REM density compared to control subjects.…”

“…All subjects in this study also participated in our previous study with metyrapone (Neylan et al, 2003).…”

“…One possible explanation for failing to find reduced delta sleep in PTSD relates to the poor sensitivity of visual sleep staging, or sleep macroarchitecture, in quantifying delta sleep. Indeed, the only two studies that applied quantitative measures of delta sleep have found decreased delta sleep in patients with PTSD (Neylan et al, 2003;Woodward et al, 2000).…”

“…Delta sleep is believed to be the primary marker for sleep homeostasis and the restorative function of sleep (Borbely and Achermann, 2000). Multiple studies have shown that increased hypothalamic corticotropin-releasing factor (CRF) release is associated with disturbed sleep and particularly with decreased delta sleep activity (reviewed in Neylan et al, 2003). In turn, treatment with a CRF receptor antagonist increased delta sleep in depressed patients (Held et al, 2004).…”

Pathological Responses to Terrorism

“…In a strong demonstration of this possibility, Southwick et al (1997) demonstrated that in certain PTSD patients, panic attacks and flashbacks were elicited by manipulation of the noradrenergic system with yohimbine, whereas in others, they were elicted by manipulation of serotonergic neurotransmission with mCPP. Certainly, PTSD has been associated with numerous other biologic alterations including immune (Wong, 2002), catecholaminergic , psychophysiologic (Orr, 1997) alterations, and changes in sleep architecture (Neylan et al, 2003). Importantly, both structural and functional neuroimaging studies of PTSD have demonstrated changes in brain volume and/or activation in regions such as the hippocampus and the amygdala (Rausch et al, 1997).…”