*4.1. GC Treatments*

PTSD treatments using GR as a mediator have been tested for use as secondary prevention, that is to say, on exposure to a TE [54]. Based on studies which show that low peritraumatic cortisol constitutes a risk factor for PTSD development, GCs could be of benefit if administered immediately after the TE [170–173], especially in the case of individuals with this additional risk factor. A large randomised control study found that traumatic injury patients who received hydrocortisone within 12 h after trauma for 10 days reported fewer PTSD symptoms during the first three months post trauma than did patients who received a placebo [174]. On the other hand, GC antagonists could also be useful, based on the role of GCs in the consolidation of the traumatic memories [42]. As GC actions influence so many functions in the brain [46], the development of synthetic GCs or other GC action modulators with increased tissue/cell/molecular pathway selectivity could be of grea<sup>t</sup> benefit for patients, as they would act on the specific PTSD HPA axis-related pathophysiological mechanism [54,112]. However, research is still far from finding such "chirurgical" treatments.

Several clinical trials are currently being carried out with substances which aim to influence the HPA axis in PTSD patients [112]. These trials are supported by studies such as that by Aerni et al. [175]—a pilot study which found that a low dose of hydrocortisone administered over three months reduce re-experiencing and avoidance symptoms in PTSD patients, based on the assumption that elevated cortisol levels which inhibit memory retrieval in healthy human subjects can also reduce the excessive retrieval of traumatic memories and related symptoms in patients with chronic PTSD. Unfortunately, other larger placebo-controlled randomised trials targeting several HPA axis-related PTSD pathophysiological mechanisms did not achieve the same promising results [176–178].

Furthermore, hydrocortisone supplementation of prolonged exposure therapy for PTSD in military veterans has been associated with a lower dropout rate and greater reduction in total PTSD symptoms, when compared to a placebo [179]. Responders to hydrocortisone supplementation had the highest pre-treatment GC sensitivity, which decreased as symptoms improved.

Because *FKBP5* SNPs, methylation, and expression variation have all been consistently associated with PTSD pathophysiology, *FKBP5* is a potential treatment target, as it confers risk for abnormal fear extinction learning in humans [180].

A recent study by Pape et al. [181], which investigated the CRHR1 antagonist GSK561679 in female PTSD patients supports the possible role of *CRHR1* methylation levels as an epigenetic biomarker to follow response to CRHR1 antagonist treatment in specific subgroups. Moreover, pre-treatment *NR3C1* methylation levels may be useful as a potential biomarker to predict PTSD treatment outcome [33].
