*5.2. Future Directions*

Psychiatric disorders are multi-determined and have a complex pathophysiology and multiple phenotypic expressions, and therefore any information which could help tailor treatments should be pursued—in particular longitudinal gene x psychotherapy interaction studies.

In the case of PTSD, most of the psychotherapeutic interventions that have been studied are short-term, limited interventions. It would be interesting to study the e ffects of intensive interventions, which require treatments of more than once a week, with no time limits (e.g., psychoanalysis—which implies 3–5 sessions a week, also with no time limit). These interventions would address not only Daskalakis et al.'s [190] hit-3 environmental challenges, but also hit-2 early-life environmental exposure. What would be the changes in HPA axis biomarkers (endophenotypes) and the epigenetic changes? Would an association or interaction with SNPs of genes regulating HPA axis be found? Further research regarding the interactions between psychotherapy and the epigenome are warranted.

Studies are needed which focus on genetic makeup and their functional correlates, which can identify endophenotypes that constitute relevant mediators or moderators of treatment e fficacy. A limited number of studies examine mRNA expression in relation to epigenetic modifications in patients with PTSD. This research is important, in order to find functional correlates between methylation patterns and phenotypic variability [71]. A better selection of the region to study DNA methylation also needs to be pursued, as well as other epigenetic mechanisms and their functional correlates [71,110]. In addition, larger samples should be studied to increase the study's power with randomised control trial approaches. Genome-wide studies of therapy responses would be ideal.

In the future, it should be possible to integrate di fferent biomarkers—including SNPs, the epigenome, and gene expression profiles—with clinical variability and psychotherapeutic armamentarium with the objective to better inform those clinicians who practice personalised/patient-centred care for this complex and challenging disorder of PTSD.

**Author Contributions:** Conceptualisation, I.C.-V.; supervision, D.C.; methodology, I.C.-V.; visualisation, I.C.-V.; writing—original draft preparation, I.C.-V.; writing—review and editing, I.C.-V. and D.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was partially supported by the Associação dos Amigos do Serviço de Endocrinologia do Hospital de São João.

**Conflicts of Interest:** None of the authors have any conflict of interest to disclose.
