noradrenergic activity and enhanced long-term memory, and Cahill et al. (1994) reported that propranolol blocked enhanced memory of an arousing story. However, it is important to note that evidence has shown that propranolol can block extinction of fear-related memories (Cain et al. 2004). Taken together, the above evidence suggests that at least a subgroup of people with PTSD has increased responsivity of the sympathetic nervous system that is most clearly evident when people are restressed (Southwick et al. 1995).
That cortisol concentrations are increased during stress and that the magnitude of stress response is associated with the magnitude of increases in cortisol led to the hypothesis that cortisol would be increased in PTSD. However, the first report, 20 years ago, of cortisol in PTSD yielded counterintuitive results: the mean 24-hour urinary excretion of cortisol was lower in patients with PTSD than in other psychiatric patients (Mason et al. 1986).
Ambiguity has persisted in the literature regarding the direction of any PTSD, associated change in cortisol concentrations as some investigators have reported increased urinary cortisol excretion in PTSD. Yehuda et al. (2002) noted that PTSD is associated with a dysregulation of the cortisol response rather than with a clear-cut directional response (cortisol that is “too low” or “too high”). Present evidence supports the hypothesis that pre-existing low cortisol is associated with increased risk of PTSD. Several recent studies have found that trauma victims who develop PTSD have lower initial cortisol responses to a traumatic event than do trauma victims who do not develop PTSD (McFarlane 1997; Resnick et al. 1997). In combat veterans with chronic PTSD, low plasma cortisol has been recorded throughout the day and night, especially in the early morning and late evening (Yehuda et al. 2002). Finally, in a randomized double-blind placebo-controlled study, Schelling et al. (2001, 2006) assessed the effect of hydrocortisone administered during septic shock. Physiologically stressful doses of hydrocortisone did have a moderately protective effect against PTSD.
Receptor-binding studies have found higher numbers of glucocorticoid receptors in subjects with PTSD than in controls without PTSD (Yehuda 1997; Yehuda et al. 1995). As discussed in Chapter 4, an increased number of receptors would enhance sensitivity by providing more binding sites for cortisol. It is consistent with increased receptor number and sensitivity that subjects with PTSD hyperrrespond to administration of dexamethasone, a synthetic glucocorticoid that acts like cortisol (Yehuda 1997; Yehuda et al. 2004). Usually, when dexamethasone is administered to healthy people, it engages glucocorticoid receptors that serve as part of a negative feedback mechanism. When engaged, the receptors signal the hypothalamus and pituitary to decrease the release of corticotropin-releasing hormone (CRH) and corticotropin; this results in decreased stimulation of the adrenal gland and diminished release of endogenous cortisol. In several different populations of trauma survivors with PTSD, dexamethasone has had an exaggerated effect and endogenous cortisol release has been reduced to a greater degree than in healthy controls. The HPA-axis findings in PTSD differ markedly from findings in studies of major depressive disorder, in which cortisol tends to be increased, and the cortisol response to dexamethasone reduced.
Additional findings in subjects with PTSD include increased CRH in cerebrospinal fluid (Baker et al. 1997; Bremner et al. 1997), blunted corticotropin response to CRH infusion (Smith et al. 1989), and increased corticotropin response to metyrapone (Yehuda et al. 2004). Those findings are consistent with studies in primates that have experienced early-life stress (Coplan et al. 1996). Animal data on the effects of a nonpeptide CRH receptor-1 antagonist (antalarmin)