*5.1. Clinical Implications*

PTSD is associated with many vulnerability and risk factors [6]. Several pathophysiological mechanisms have been hypothesised [54], which make this disorder phenotypically so diverse [19], and thus, treatments must inevitably be tailored, as we are now considering this disorder to be a gene–trauma–epigenetic interactions paradigm (Figure 3) [155].

**Figure 3.** Gene/environment interaction in PTSD. Ranging from genetic and environment interactions through to symptoms, possible biomarkers and brain and hormonal changes. Abbreviations: HPA axis: hypothalamic–pituitary–adrenal axis; GR: glucocorticoid receptor. Adapted from [209].

Evidence is mounting that the HPA axis is implicated in PTSD pathophysiology and that interventions aiming to a ffect this system are showing increased usefulness for treatment interventions and can inform treatment outcomes—particularly psychotherapeutic interventions [e.g., 33,138,194].

We hope to have made it clear that traumatic experiences interact with the genetic makeup in several ways during human development. One of these is through modifications of the epigenome conditioning of the pathophysiology of many disorders—including PTSD. However, probably the most important message is that this interaction can occur reversely, through psychotherapeutic interventions which, if tailored according to the pathophysiological mechanisms, could be more useful for those individuals who su ffer, and more cost-e ffective for all [33], although further studies need to be carried out to inform us better what works best, and for whom. If we could predict which patients would improve better with which type of treatment, then the level of su ffering, time, and resources could be significantly reduced for such a complex and heterogeneous disorder. However, as promising and

appealing the results of the studies reviewed in this paper might be, there is still a long way before they attain clinical applicability.

Furthermore, psychotherapy delivered perinatally with modifications which are specific to the perinatal period and are focussed on parenting are necessary for the prevention of PTSD intergenerational transmission [210], as PTSD influenced parent-child interactions are important and potentially modifiable contributors [211]. Evidence-based psychotherapy o ffers considerable advantages for perinatal PTSD, based on the potential teratogenic e ffects of typically-recommended medications for PTSD [212]. Furthermore, epigenetic modifications associated with PTSD are subject to inheritance [105]. If these epigenetic modifications could be reversed by psychotherapy, this would then constitute another way to break the intergenerational transmission of PTSD.

The studies mentioned in this review used psychotherapy for PTSD secondary or tertiary prevention or treatment, however, as it is known that there is a genetic risk for exposure to TEs, a primary psychotherapeutic intervention might also be useful, mainly for those individuals with other cumulative risk factors, such as childhood adversity or parental psychiatric disorders [6]. Furthermore, this review can also be useful to support the importance of trauma-informed care as a patient-centred approach which is needed in clinical practice and which can prevent many forms of trauma-related su ffering [213].
