Oxytocin receptor is a potential biomarker of the hyporesponsive HPA axis subtype of PTSD and might be modulated by HPA axis reactivity traits in humans and mice.

This study aimed to identify yet unavailable blood biomarkers for the responsive and the hyporesponsive hypothalamic-pituitary-adrenal (HPA) axis subtypes of posttraumatic stress disorder (PTSD). As, I, we recently discovered the intranasal neuropeptide oxytocin to reduce experimentally provoked PTSD symptoms, II, expression of its receptor (OXTR) has hitherto not been assessed in PTSD patients, and III, oxytocin and OXTR have previously been related to the HPA axis, we considered both as suitable candidates. During a Trier Social Stress Test (TSST), we compared serum oxytocin and blood OXTR mRNA concentrations between female PTSD patients, their HPA axis reactivity subtypes and sex and age-matched healthy controls (HC). At baseline, both candidates differentiated the hyporesponsive HPA axis subtype from HC, however, only baseline OXTR mRNA discriminated also between subtypes. Furthermore, in the hyporesponsive HPA axis subgroup, OXTR mRNA levels correlated with PTSD symptoms and changed markedly during the TSST. To assess the influence of (traumatic) stress on the cerebral expression of oxytocin and its receptor and to test their suitability as biomarkers for the mouse PTSD-like syndrome, we then analyzed oxytocin, its mRNA (Oxt) and Oxtr mRNA in three relevant brain regions and Oxt in blood of a PTSD mouse model. To further explore the HPA axis reactivity subtype dependency of OXTR, we compared cerebral OXTR protein expression between mice exhibiting two different HPA axis reactivity traits, i.e., FK506 binding protein 51 knockout vs. wildtype mice. In summary, blood OXTR mRNA emerged as a potential biomarker of the hyporesponsive HPA axis PTSD subtype and prefrontal cortical Oxtr and Oxt of the mouse PTSD-like syndrome. Moreover, we found first translational evidence for a HPA axis responsivity trait-dependent regulation of OXTR expression. The lack of a cohort of the (relatively rare) hyporesponsive HPA axis subtype of HC is a limitation of our study.

MMP9 mRNA is a potential diagnostic and treatment monitoring marker for PTSD: Evidence from mice and humans.

Although matrix metalloproteinase 9 (MMP9) has been found associated with various psychiatric disorders and with threat memories in humans, its role in post-traumatic stress disorder (PTSD) and related animal models is understudied. Thus, we analyzed MMP9 mRNA expression kinetics during two different stress experiments, i.e., the Trier Social Stress Test and the dexamethasone suppression test (DST), in whole blood of two independent cohorts of PTSD patients vs. non-traumatized healthy controls (HC) and, moreover, in a mouse model of PTSD and in dexamethasone-treated mice. Besides MMP9, we quantified mRNA levels of four of its regulators, i.e., interleukin (IL)-1 receptor 1 and 2 (IL1R1, IL1R2), IL-6 receptor and tumor necrosis factor receptor 1 (TNFR1) in 10 patients exposed to the DST before vs. after successful PTSD psychotherapy vs. 13 HC and, except from Il6r, also in different brain regions of the PTSD mouse model. We are the first to show that blood MMP9 mRNA concentrations were elevated after acute dexamethasone in PTSD patients, improved upon partial remission of PTSD and were, furthermore, also elevated, together with its regulator Tnfr1, in the prefrontal cortex of PTSD-like mice. In contrast, blood TNFR1 and IL1R2 were markedly underexpressed in PTSD patients. In conclusion, we found translational evidence supporting that, I, TNFR1 and MMP9 mRNA expression might be involved in PTSD pathobiology, II, might constitute potential diagnostic blood biomarkers for PTSD and, importantly, III, post-dexamethasone blood MMP9 hyperexpression, which speculatively results from post-dexamethasone underexpression of IL1R2, might serve also as potential treatment monitoring biomarker for PTSD.

Posttraumatic growth during cognitive behavioural therapy for posttraumatic stress disorder: Relationship to symptom change and introduction of significant other assessment.

Posttraumatic growth (PTG) may play a role in the treatment of posttraumatic stress disorder (PTSD) as it is supposed to have either beneficial or dysfunctional effects on treatment-related PTS symptom (PTSS) changes. This study examined whether cognitive behavioral therapy (CBT) for PTSD patients can foster PTG assessed by self-reports and reports from significant others. Forty-eight PTSD patients participating in trauma-focused CBT were assessed twice: at the beginning of therapy (T1) and after 3 months of therapy (T2, N = 34). We used the Clinician Administered PTSD Scale and the Posttraumatic Growth Inventory (PTGI), and constructed a significant other version of the PTGI (PTGI-SOA). The PTSS severity declined during the course of treatment, whereas PTG levels remained stable. Both the PTGI and PTGI-SOA were associated with higher PTSS reduction at T2. The results suggest that PTG is associated with greater improvement in PTSS during trauma-focused CBT, even though treatment could not directly enhance PTG. Significant other assessments seem to be a promising approach to improve PTG measurement.

PTSD psychotherapy improves blood pressure but leaves HPA axis feedback sensitivity stable and unaffected: First evidence from a pre-post treatment study.

Although key to development of tailored drugs for augmentation treatment of psychotherapy for posttraumatic stress disorder (PTSD), the biological correlates of PTSD remission are still unknown, probably because pre-post treatment studies searching for them are rare. Not even the feedback sensitivity of the otherwise well-studied hypothalamic-pituitary-adrenal (HPA) axis nor arterial blood pressure (BP), which was previously reported to be elevated in PTSD patients, have so far been analyzed during PTSD treatment. To narrow this knowledge gap, we first performed an overnight dexamethasone suppression test (DST) in a mixed-sex cohort of 25 patients with severe PTSD vs. 20 non-traumatized healthy controls (nt-HC). In addition to hormones, BP and heart rate (HR) were measured at each of the four assessment points (APs). Second, the same parameters were assessed again in 16 of these patients after 12 sessions of integrative trauma-focused cognitive behavioral therapy (iTF-CBT). In relation to nt-HC, PTSD patients showed a significant elevation in HR and diastolic BP while their systolic BP, DST outcomes and basal serum cortisol levels (BSCL) were not significantly altered. In response to iTF-CBT, PTSD symptoms and dysfunctional stress coping strategies improved significantly in PTSD patients. Most important, also their systolic and diastolic BP levels ameliorated at distinct APs while their DST outcomes and BSCL remained unchanged. To our knowledge, this is the first pre-post treatment study assessing the stability of the DST outcome and BP levels during PTSD treatment. Our results provide first evidence for a non-involvement of HPA axis feedback sensitivity in PTSD symptom improvement and, furthermore, suggest a possible role for BP-regulating pathways such as the sympathetic nervous system in PTSD remission. Limitations arise from the small sample size, the lack of an untreated patient group and drug treatment of patients.

Posttraumatic Growth in Populations with Posttraumatic Stress Disorder-A Systematic Review on Growth-Related Psychological Constructs and Biological Variables.

Posttraumatic growth (PTG) and Posttraumatic Stress Disorder (PTSD) are possible consequences of trauma. PTG is supposed to emerge from cognitive processes and can have functional and dysfunctional aspects. This systematic review aims to identify and evaluate publications assessing PTG in adults diagnosed with PTSD in order to analyse the relationship between both constructs, how PTG is related to specific psychological variables and if there are biological variables linked to PTG. This extended review evaluates the quality of measures applied and is the first to study PTG only in populations meeting full PTSD criteria. In addition, the relationship between PTG and other relevant constructs, such as openness, optimism and social support, is explored. Our systematic literature search identified 140 studies of which 19 fulfilled our inclusion criteria; most of them used the Post-Traumatic Growth Inventory. Results indicate that trauma survivors with PTSD exhibit more PTG than those without PTSD and that PTG can be intensified during the therapeutic process whereat it is unclear whether PTG is a desirable outcome of PTSD therapy. Positive correlations between PTG and PTSD are reported. For diagnosed populations, we could not find strong evidence of a quadratic relationship between PTG and PTSD, although some studies support this hypothesis. Findings regarding the association of PTG with psychological variables are heterogeneous. Only one study focused on PTG as well as on biological variables (salivary cortisol) but did not discuss possible links between these two so far unconnected research fields in PTSD. Copyright © 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Trauma survivors with PTSD develop more PTG than those without PTSD, it remains unclear whether PTSD and PTG are curvilinearly related. PTG can be enhanced through PTSD therapy, nevertheless one must not assume that PTG is a favorable treatment outcome since we do not know if the development of PTG during therapy promotes the reduction of PTSD symptoms. It is unclear whether PTG in PTSD sufferers is a constructive outcome of cognitive processes or a positive illusion in favor of avoidance and denial. Results regarding the association of personality factors, social support and PTG are inconsistent, studies on biological aspects of PTG are lacking.

Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity.