Cortisol response to traumatic stress to predict PTSD symptom development – a systematic review and meta-analysis of experimental studies

Background: Pre-and post-traumatic hypothalamic–pituitary–adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events. Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms. Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (dSMC) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms. Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (kobservations = 25, dSMC = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = −.18 [−.35; −.01]), higher state happiness (k = 8, r = −.34 [−.59; −.03], variable inverted) and lower state anger (k = 9, r = −.14 [−.26; −.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = −.20 [−.33; −.06]) and lower state sadness (k = 17, r = −.16 [−.25; −.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]). Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms

Associations between oxytocin and vasopressin concentrations, traumatic event exposure and posttraumatic stress disorder symptoms: group comparisons, correlations, and courses during an internet-based cognitive-behavioural treatment

Background: Posttraumatic stress disorder (PTSD) is characterized by impairments in extinction learning and social behaviour, which are targeted by trauma-focused cognitive behavioural treatment (TF-CBT). The biological underpinnings of TF-CBT can be better understood by adding biomarkers to the clinical evaluation of interventions. Due to their involvement in social functioning and fear processing, oxytocin and arginine vasopressin might be informative biomarkers for TF-CBT, but to date, this has never been tested. Objective: To differentiate the impact of traumatic event exposure and PTSD symptoms on blood oxytocin and vasopressin concentrations. Further, to describe courses of PTSD symptoms, oxytocin and vasopressin during an internet-based TF-CBT and explore interactions between these parameters. Method: We compared oxytocin and vasopressin between three groups of active and former male service members of the German Armed Forces (n = 100): PTSD patients (n = 39), deployed healthy controls who experienced a deployment-related traumatic event (n = 33) and non-deployed healthy controls who never experienced a traumatic event (n = 28). PTSD patients underwent a 5-week internet-based TF-CBT. We correlated PTSD symptoms with oxytocin and vasopressin before treatment onset. Further, we analysed courses of PTSD symptoms, oxytocin and vasopressin from pre- to post-treatment and 3 months follow-up, as well as interactions between the three parameters. Results: Oxytocin and vasopressin did not differ between the groups and were unrelated to PTSD symptoms. PTSD symptoms were highly stable over time, whereas the endocrine parameters were not, and they also did not change in mean. Oxytocin and vasopressin were not associated with PTSD symptoms longitudinally. Conclusions: Mainly due to their insufficient intraindividual stability, single measurements of endogenous oxytocin and vasopressin concentrations are not informative biomarkers for TF-CBT. We discuss how the stability of these biomarkers might be increased and how they could be better related to the specific impairments targeted by TF-CBT

Der Einfluss des Menstruationszyklus auf depressive Symptome und Stress

Background: The risk of developing a depressive disorder is twice as high for women as for men. This sex disparity emerges in puberty and ends at menopause, a time frame during which most women have a menstrual cycle. This suggests that the menstrual cycle and fluctuating ovarian hormones might contribute to the development of depressive disorders. In turn, ovarian hormones interact closely with one of the two major physiological stress regulators, the hypothalamus-pituitary-adrenal (HPA) -axis. Therefore, the interaction between all three entities - the menstrual cycle, depression, and stress markers – is close at hand and object of this dissertation. Methods: Firstly, the relationship between the menstrual cycle and depressive symptoms is explored by investigating if and how depressive symptoms change across the menstrual cycle in participants with and without a depressive disorder (study 1) and whether menstrual cycle irregularity, specifically irregularity in length (study 2) and anovulation (study 3), interacts with depressive symptoms. This was investigated in multiple samples (adults and adolescents) through longitudinal, smartphone-based ambulatory assessments. Secondly, possible differences in biological stress marker concentrations between menstrual cycle phases were investigated. Thereby, two meta-analyses (study 4 and 5) compared cortisol as a marker for basal HPA axis activity (study 4) and its reactivity in response to acute stressors (study 5) between cycle phases. Lastly, perceived stress was investigated as a moderator of the association between ovarian hormone fluctuations and depressive symptom changes in a sample of peripubertal females using weekly measures of stress, depressive symptoms, and hormone concentrations (study 6). Results: The results indicated that depressive symptoms fluctuate in some hormone sensitive individuals, with varying intensities and patterns (peri-menstrual or mid-cycle increase of symptoms, study 1). This cycle-related fluctuation differed between single depressive symptoms, highlighting the importance of a symptom-based approach (study 1-4). Furthermore, higher depressive symptoms were observed in irregular menstrual cycles with respect to cycle length (study 2) and anovulation (study 3). When investigating differences in biological stress markers across the menstrual cycle, meta-analytic comparisons revealed small-sized effects of higher basal cortisol concentrations (study 5) and lower cortisol reactivity (study 6) in response to stressors in the follicular phase compared to the luteal phase. Finally, subjective stress moderated the direction of the association between hormone fluctuations and depressive symptoms. Specifically, in a high-stress context, hormone surges were linked to symptom increases whereas in a low-stress context, hormone withdrawals were linked to symptom increases. Discussion: This dissertation presented a collection of interconnected studies that highlight that hormone fluctuations across the menstrual cycle are interconnected with stress and depressive symptoms. Possible biological explanations include a differential sensitivity of GABAA-receptors to allopregnanolone, but this needs further investigations. Implications for future research involve the improvement of screening tools for individuals sensitive to hormone fluctuations and the development of treatment options for premenstrual exacerbation of depression. The generalizability of the results might be limited, as only one cycle per individual was investigated for relatively small samples in the primary studies. This was compensated by highly frequent assessments throughout the cycle and meta-analyses to increase power. Further strengths of this dissertation include a variety of investigated age groups, samples from multiple countries, and a multimethodological approach across the six studies, including primary studies using biological markers and psychological assessments, meta-analyses, and guidelines for future studies. Additionally, the studies were preregistered, analyses scripts were made openly accessible, and existing guidelines were adhered to. In conclusion, it is essential to include the menstrual cycle and ovarian hormone fluctuations and their interconnection to stress in future research on depression. Identifying female-specific risk factors of depression is crucial to provide individualized and more effective treatment options and to improve the overall understanding of stress-related mental disorders

R Markdown

This segment contains the R markdown for the analyses and the data set used in the meta-analysi

HPA axis regulation in posttraumatic stress disorder: A meta-analysis focusing on potential moderators

Posttraumatic stress disorder (PTSD) is often associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Previous findings are inconsistent, possibly due to trauma exposure of controls or different hormone measurement methods. We investigated cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) in adults with clinical PTSD under basal or challenged conditions (Prospero registration no. CRD42016041690). A search of PubMed, Scopus, Medlin, PsycINFO, Pilots/ProQuest, and Web of Science resulted in 108 included studies (N = 6484). Morning and 24 h cortisol were significantly lower in PTSD than in controls (g = - 0.21; 95% CI: -0.42-( - 0.01); g= -0.31; CI: - 0.60-( - 0.03)). Significant cortisol increases occurred after awakening in PTSD (g = 0.40; CI: 0.13-0.67) and in non-exposed controls (g = 0.96; CI: 0.59-1.33). Evening DHEA was significantly higher in PTSD than in non-exposed controls (g = 0.58; CI: 0.17-0.99). All groups showed large cortisol suppression effects after dexamethasone administration. Overall, the potential moderators investigated did not reveal a consistent pattern of HPA alterations

The Effect of an Internet-Based Intervention for Depression on Cortisol and Alpha-Amylase

Introduction: Psychotherapeutic interventions for major depressive disorder (MDD) have been suggested to be associated with a normalization of biological stress system (i.e., the hypothalamic-pituitary-adrenal axis and the autonomic nervous system) dysregulation. Furthermore, pre-intervention cortisol parameters have been identified as prescriptive biological markers of treatment success. However, evidence of treatment effects on the biological stress systems is still sparse, and results are heterogeneous. The current study examined the effect of an internet-based intervention for MDD on salivary cortisol and alpha-amylase as well as hair cortisol concentrations. Moreover, the prescriptive capacity of pre-intervention cortisol and alpha-amylase concentrations on treatment response was explored. Methods: Thirty-eight participants suffering from mild to moderate MDD collected saliva and hair samples throughout the intervention. Biological outcome parameters were salivary cortisol and alpha-amylase (awakening response, total diurnal output, diurnal slope) and hair cortisol concentrations. Treatment response was indicated by change in depression severity and perceived chronic stress. Results: Treatment response on depression scores or chronic stress was not associated with changes in any of the cortisol or alpha-amylase parameters. Exploratory analysis indicated that non-responders showed a steeper alpha-amylase slope pre-intervention. Discussion: The results indicate that changes in depressive symptoms did not correspond to changes of the biological stress systems, contradicting the suggested normalization of dysregulated hypothalamic-pituitary-adrenal axis or autonomic nervous system activity through a psychotherapeutic intervention. However, the results point to a potential role of pre-intervention alpha-amylase slope as a prescriptive marker of treatment response for depression

Trauma exposure, posttraumatic stress disorder and oxytocin: A meta-analytic investigation of endogenous concentrations and receptor genotype

Oxytocin's stress-reducing and social functions suggest an involvement in trauma processing and posttraumatic stress disorder (PTSD). We searched PubMed, PubPsych, PsycINFO, PsycARTICLES, Web of Science, ProQuest and ClinicalTrials.gov for studies assessing endogenous oxytocin, oxytocin receptor genotype or methylation in traumatized humans. Eligible studies (k = 66) were systematically described. We meta-analytically compared oxytocin parameters between traumatized and non-traumatized individuals (k = 17) and individuals with and without PTSD (k = 8), and correlated oxytocin with trauma exposure (k = 16) and PTSD symptoms (k = 8). Endogenous oxytocin concentrations did not differ between PTSD patients and healthy individuals. The remaining effects on endogenous oxytocin were heterogeneous. Subgroup analyses identified sampling-related, trauma-related and demographic moderators, resulting in inconsistent or non-significant effects. Methylation data were insufficient for meta-analyses, and meta-analytic genotype results were inconsistent. Unstimulated endogenous oxytocin was not a biomarker for trauma exposure or PTSD. Given the impact of methodology, more basic research on endogenous oxytocin measurements is needed. Future studies might consider the oxytocin stress response and investigate oxytocin longitudinally

HPA axis activity across the menstrual cycle - a systematic review and meta-analysis of longitudinal studies

Differential HPA axis function has been proposed to underlie sex-differences in mental disorders; however, the impact of fluctuating sex hormones across the menstrual cycle on HPA axis activity is still unclear. This meta-analysis investigated basal cortisol concentrations as a marker for HPA axis activity across the menstrual cycle. Through a systematic literature search of five databases, 121 longitudinal studies were included, summarizing data of 2641 healthy, cycling participants between the ages of 18 and 45. The meta-analysis showed higher cortisol concentrations in the follicular vs. luteal phase (dSMC = 0.12, p = .004, [0.04 – 0.20]). Comparisons between more precise cycle phases were mostly insignificant, aside from higher concentrations in the menstrual vs. premenstrual phase (dSMC = 0.17, [0.02 – 0.33], p = .03). In all included studies, nine samples used established cortisol parameters to indicate HPA axis function, specifically diurnal profiles (k = 4) and the cortisol awakening response (CAR) (k = 5). Therefore, the meta-analysis highlights the need for more rigorous investigation of HPA axis activity and menstrual cycle phase

Sex and gender differences in risk factors for post-traumatic stress disorder: a systematic review and meta-analysis of prospective studies

This project was pre-registered: https://osf.io/jnzf