**1. Introduction**

Post-traumatic stress disorder (PTSD) is a trauma- and stressor-related disorder which can only develop after the experience of a major traumatic event (TE) [1]. In the fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [1], PTSD criteria were redefined and are now characterised by four symptom clusters, namely: re-experience of the TE; avoidance of stimuli associated with the TE; negative cognitions and mood; and alterations in arousal, all of which must last for more than one month and cause significant clinical distress or impairment in important areas of functioning. Although the experience of TEs is very frequent in the population, with a lifetime prevalence ranging from 64–90% [2,3], only around 10% of the population will develop the disorder [4]. PTSD development is highly dependent on the type of TE, the individual genetic makeup, and other risk factors, as is also the manifestation of different symptoms and the severity of PTSD [5,6].

When an individual experiences a TE, the stress-reactive systems are activated, which include the sympathoadrenomedullary drive and the hypothalamic–pituitary–adrenal (HPA) axis [7]. Individuals with a history of previous increased vulnerability to PTSD development (e.g., childhood adversities which modify the stress-reactive systems [8,9]) can experience PTSD symptoms immediately after the TE experience, or later on, while those with no such vulnerability can develop PTSD due to specific direct TE-related e ffects on the stress systems (e.g., epigenetic modifications or trauma interaction with specific single nucleotide polymorphisms (SNPs)).

The reason why only a limited number of people who experienced TEs develop PTSD has been subject to debate in the scientific community [10]. Gene/environment (G × E) interactions have been indicated as reliable mechanisms [11]. Indeed, it appears that vulnerability to develop PTSD can result from exposure to environmental adversity in cases of specific genetic makeup, such as, for example, SNPs and the epigenome [12]. TEs can also influence genetic expression through epigenetic mechanisms. Furthermore, exposure to other previous adverse experiences increases the risk of PTSD development [13], through epigenetic mechanisms [8]. SNPs can also interact with environmental exposure and epigenetic modifications to increase the risk of PTSD development [14].

A recent systematic review found that the examination of all the included PTSD studies consistently implicated DNA methylation and gene expression changes in the HPA axis and inflammatory genes in PTSD pathophysiology [15]. Indeed, genetic factors have been estimated to account for 30–46% of the variance in PTSD [16,17]. Being a stress-related disorder, HPA axis regulator genes have been extensively studied—such as the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP5) genes [10]. Although the risk of developing PTSD is polygenetic, a recent meta-analysis found SNPs in these two genes to be associated with PTSD [18]. Furthermore, the GR gene (*NR3C1*) has been considered to be a candidate gene which underlies the neurobiological-related glucocorticoid (GC) processes involved in the development or maintenance of PTSD [12].

PTSD is a heterogeneous disorder and the determinants of di fferent conditional risks for PTSD development can be categorised in several ways [19], including the type and burden of the TE and the sex and age of the exposed subject, which also determine the symptomatic expression, clinical trajectories, co-morbidity, and treatment response. Furthermore, the HPA axis regulation of the response to TE and stress is highly complex and is subject to a large degree of variability.

As a result, different clinical trajectories of PTSD development have been described in different trauma-exposed populations [10,20–23]. The longer-lasting prospective study found five classes of trajectories based on PTSD symptom severity, which were assessed using the Clinician-Administered PTSD Scale score, during the six years after traumatic injury. These are: chronic (4%), recovery (6%), worsening/recovery (8%), worsening (10%), and resilient (73%) [21]. In addition, PTSD can be very debilitating and is also associated with mental and somatic comorbidity [24,25], such as depression, substance use disorders, cardiovascular conditions, and endocrine and metabolic disorders, as well as with intergenerational transmission of depression, emotion dysregulation, and HPA axis dysfunction [26–28].

Several treatments have been indicated for patients with PTSD, which mainly include pharmacotherapy and psychotherapy. As pharmacotherapy approaches have considerable high rates of non-response, significant investment has been carried out in applying other therapies—particularly psychotherapies. Various psychotherapies have been indicated for the treatment of PTSD, with reported success being superior to that of the prescription of medication in several studies [29], although their e ffectiveness has been questioned [30]. Accordingly, there is a need to improve existing PTSD psychotherapeutic treatments, as almost two-thirds of patients receiving prolonged exposure therapy (PE) or cognitive processing therapy (CPT)—which are the two most widely-recommended first-line therapies—maintained the same diagnosis posttreatment [31].

It is becoming clearer that psychotherapeutic interventions must be individually tailored. Psychotherapeutic intervention in patients with PTSD has been associated with change in plasma cortisol [32], and more recently with changes in the epigenome [33,34]. Furthermore, SNPs in the GR and *FKBP5* genes and *FKBP5* epigenomic alterations predict psychotherapeutic outcomes [33,35,36]. Another ten genes, including a gene related with stress vulnerability (*ZFP57*), have also been recently associated with psychotherapeutic outcomes in a longitudinal study of genome-wide DNA methylation levels [34]. Successful treatment of PTSD patients with psychotherapy was accompanied by changes in DNA methylation.

In this paper we aim to review the extant knowledge regarding the interplay between the HPA axis regulatory genes and psychotherapeutic interventions for patients with PTSD, by taking into account the previously-reported HPA axis-related G × E interactions involved in PTSD pathophysiology, as well as the interactions between the genetic makeup and psychotherapy and the urgen<sup>t</sup> need to improve patients' psychotherapeutic outcomes.
